The insulin/insulin-like growth factor (IGF)-axis is a major regulator of cell proliferation/survival, and circulating IGF-axis protein levels are associated with the risk of several solid tumors, including tumors of the breast and prostate. Little is known, however, regarding the IGF-axis's relation with cervical cancer, the second most common cancer in women worldwide. To our knowledge, the only prospective data come from our small pilot investigation. That study found associations of IGF-axis protein levels with persistence of oncogenic human papillomavirus (HPV), and with oncogenic HPV+ cervical lesions. Those lesions, though, were almost all low grade. A study that demonstrates a relationship between IGF-axis levels and incident cervical pre-cancer (CIN- 2+) is needed before more comprehensive, costly studies (e.g., with paired serum/tissue and repeated testing) are conducted. Briefly, IGF-I is a hormone with mitogenic/anti-apoptotic activity, and most cells express the IGF-I receptor. Down-regulation of the IGF-I receptor can even reverse the transformed phenotype of cervical cancer cell lines. In contrast, IGF binding protein (IGFBP)-3, the most abundant IGFBP, has both direct (IGF-I independent) and indirect (sequestering IGF-I) anti-mitotic/pro-apoptotic effects. Nonetheless, there have been few human studies of the IGF-axis and HPV/cervical neoplasia, and the prior data (all cross-sectional) were inconsistent. Therefore, as above, we conducted a small prospective pilot study of the IGF-axis and HPV natural history in 137 women. Persistence of oncogenic HPV was associated with increasing IGF-I/IGFBP-3 ratio (HR= 7.1;1.8-25), while increasing IGFBP-3 was associated with low risk of oncogenic HPV+ cervical neoplasia (HR=0.07;0.01-0.66). We also note that obesity has been associated with risk of cervical cancer in some studies. We hypothesize that this relationship is due to the prevalence of hyperinsulinemia in obese women, since insulin has amino acid sequence homology, as well as mitogenic/anti-apoptotic activity, in common with IGF-I. If correct, the insulin/IGF-axis might be exploited in the treatment of cervical cancer and, moreover, in cervical cancer screening. To study the insulin/IGF-axis in cervical tumorigenesis we propose a case-cohort study set in one of the few large, truly population-based cohort investigations of cervical disease, called the Guanacaste Project (GP) (N=7,278), established by NCI/NIH. Specifically, we will measure baseline serum levels of IGF-I, IGF-II, IGFBP-3, and C-peptide (a surrogate marker of insulin that does not require fasting blood), in N=182 GP women with persistent oncogenic HPV, and N=142 with incident cervical pre-cancer (i.e., CIN-2 or worse). A random subcohort selected at baseline (N=900) will be used as the comparison group. These cumulative data will then be used to address three Aims: To determine the associations of IGF-I, IGF-II, IGFBP-3, and C- peptide with (i) persistence of oncogenic HPV, and (ii) with cervical pre-cancer (our major endpoint), as well as (iii) to study insulin/IGF-axis levels and the factors associated with them in Costa Rican women, using data from the subcohort (since there is sparse insulin/IGF-axis data outside of developed countries). PUBLIC HEALTH RELEVANCE: The insulin/insulin-like growth factor (IGF)-axis is a major regulator of cell proliferation/survival, and circulating IGF-axis protein levels are associated with the risk of several solid tumors, including tumors of the breast and prostate. Little is known, however, regarding the IGF-axis's relation with cervical cancer, the second most common cancer in women worldwide. This application proposes the first prospective study of insulin/IGF-axis levels and their associations with incident cervical pre-cancer (i.e., cervical intraepithelial neoplasia [CIN]-2 or worse). If it is confirmed that the insulin/IGF-axis plays an important role in cervical tumorigenesis then the insulin/IGF-axis and its signaling pathways might be exploited in cervical cancer treatment and, moreover, in enhancing screening practices to prevent cervical cancer.